Isoform-specific hyperactivation of calpain-2 occurs presymptomatically at the synapse in Alzheimer's disease mice and correlates with memory deficits in human subjects

Ahmad, Faraz and Das, Debajyoti and Kommaddi, Reddy Peera and Diwakar, Latha and Gowaikar, Ruturaj and Rupanagudi, Khader Valli and Bennett, David A and Ravindranath, Vijayalakshmi (2018) Isoform-specific hyperactivation of calpain-2 occurs presymptomatically at the synapse in Alzheimer's disease mice and correlates with memory deficits in human subjects. In: SCIENTIFIC REPORTS, 8 .

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Abstract

Calpain hyperactivation is implicated in late-stages of neurodegenerative diseases including Alzheimer's disease (AD). However, calpains are also critical for synaptic function and plasticity, and hence memory formation and learning. Since synaptic deficits appear early in AD pathogenesis prior to appearance of overt disease symptoms, we examined if localized dysregulation of calpain-1 and/or 2 contributes to early synaptic dysfunction in AD. Increased activity of synaptosomal calpain-2, but not calpain-1 was observed in presymptomatic 1 month old APP(swe)/PS1.E9 mice (a mouse model of AD) which have no evident pathological or behavioural hallmarks of AD and persisted up to 10 months of age. However, total cellular levels of calpain-2 remained unaffected. Moreover, synaptosomal calpain-2 was hyperactivated in frontal neocortical tissue samples of post-mortem brains of AD-dementia subjects and correlated significantly with decline in tests for cognitive and memory functions, and increase in levels of beta-amyloid deposits in brain. We conclude that isoform-specific hyperactivation of calpain-2, but not calpain-1 occurs at the synapse early in the pathogenesis of AD potentially contributing to the deregulation of synaptic signaling in AD. Our findings would be important in paving the way for potential therapeutic strategies for amelioration of cognitive deficits observed in ageing-related dementia disorders like AD.

Item Type:	Journal Article
Publication:	SCIENTIFIC REPORTS
Publisher:	NATURE PUBLISHING GROUP
Additional Information:	Copy right for this article belong to NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
Department/Centre:	Division of Biological Sciences > Centre for Neuroscience
Date Deposited:	24 Sep 2018 15:38
Last Modified:	24 Sep 2018 15:38
URI:	http://eprints.iisc.ac.in/id/eprint/60684

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